Therapeutic antihistaminic suspensions



United States Patent THERAPEUTIC AN TIHISTANIINIC SUSPENSIONS Donald A. Zuck and Warren H. Rix, Indianapolis, Ind., assignors to Eli Lilly and Company, Indianapolis, Ind., a corporation of Indiana No Drawing. Application January 28, 1954, Serial No. 406,898

4 Claims. (01. 167-55) This invention relates to therapeutic preparations and more particularly to suspensions containing antihistaminic agents for oral administration.

The use of the well-known antihistaminic agents, 1 p chlorophenyl 2 phenyl 4 pyrrolidino 2- butene and N,N dimethyl N (2 thenyl) N (2- pyridyl)ethylenediamine for the relief of symptoms of allergy, hay fever or vasomotor rhinitis is well known, and those substances have been employed separately or in combination with each other or with other drugs with marked success. They are absorbed from the gastrointestinal tract and are commonly administered orally. However, because of certain side effects which are manitested by the named compounds when they come into contact with the mucous membrances, it has heretofore been found necessary to administer them in such form that they are isolated from contact with the oral tissues, such as hard gelatin capsules or coated tablets, each containing a dose of the medicament. Thus, a particularly useful combination of antihistaminic and adjuvant drugs has been found to be a mixture of 1 cyclopentyl 2- methylaminopropane hydrochloride, 1 p chlorophenyl- 2 phenyl 4 pyrrolidino 2 butene diphosphate and N,N dimethyl N (2 thenyl) N (2 pyridyl) ethylenediamine dihydrochloride. These substances, when administered together in the form of a medicament enclosed in a gelatin capsule, give prompt and lasting relief from the symptoms of allergy, and generally speaking, exhibit no untoward side elfects. However, when it was heretofore sought to administer this combination in the form of uncoated tablets or suspensions for oral administration, unpleasant if not dangerous side effects were noted. These side elfects include extremely unpalatable bitter taste, and local anesthesia of the tongue and mucous membranes of the mouth and throat. These effects were so marked as to preclude the use of the combination in any form except those in which the substances were prevented from contacting the oral tissues.

It is an object of this invention to provide a therapeutic preparation, containing certain new salts of 1 p chlorophenyl 2 phenyl 4 pyrrolidino 2 butene, N,N- dimethyl N (2 thenyl) N (2 pyridyl)ethylenediamine and 1 cyclopentyl 2 methylaminopropane, which is free from the undesirable side effects heretofore experienced. It is a further object of this invention to prepare a therapeutically useful suspension containing the named substances. Additional objects of the invention will be evident from the disclosures hereinafter made.

In accordance with the above and other objects of the invention, we have provided certain new insoluble salts of l p chlorophenyl 2 phenyl 4 pyrrolidino 2- butene, N,N dimethyl N (2 thenyl) N (2 pyridyl)ethylenediamine and 1 cyclopentyl 2 methylaminopropane, which salts are substantially insoluble in water, but which are absorbed from the gastrointestinal tract to provide the full therapeutic effects of those compounds. We have found that the o (4 hydroxybenzoyl)benzoic acid salts of N,N dimethyl N (2-v 2,718,486 Patented Sept. 20, 1955 thenyl) N (2 pyridyDethylenediamine and 1 cyclopentyl 2 methylaminopropane are crystalline substances which are insoluble in water and most organic solvents.- They are substantially tasteless and have no local anesthetic action upon the mucous membranes when administered orally. However, they are readily absorbed in the gastrointestinal tract and exert their usual physiological activity in a degree proportional to the amount of the base which is present. Similarly, we have found that the 1,5 naphthalene disulfonic acid salt of l chlorophenyl 2 phenyl 4 pyrrolidino 2 butene is insoluble in water, and is without taste, or local anesthetic action upon the mucous membranes, but when absorbed in the gastrointestinal tract, the expected physiological effect is obtained consistent with the amount of the base which is present. Because of their insoluble nature, the salts mentioned can be combined and formed into a suspension using the common pharmaceutical suspending media, and when so prepared can be administered without unpleasant local side effects. However, after the suspension is ingested and reaches the stomach the inedicaments contained therein are rapidly absorbed and exercise the desired therapeutic eflfects.

The novel insoluble salts can be used in the form of suspensions containing various amounts of the compounds. Thus, from about 1 to 6 mg. per ml. of di-(lp chlorophenyl -2 phenyl 4 pyrrolidino 2 butene)- 1,5 naphthalene disulfonate; about 2 to 10 mg. per ml. of N,N dimethyl N (2 thenyl) N (2 pyridyl)- ethylenediamine o (4 hydroxybenzoyl) benzoate and about 1 to 5 mg. per ml. of l cyclopentyl 2 methylaminopropane o (4 hydr0xybenzoyl)benzoate can be used, and are preferred ranges of concentration for the salts named. Higher concentrations of the salts can be employed if desired, where the physical size of the therapeutic suspension is to be decreased.

Therapeutic suspensions containing the novel salts can be prepared using various aqueous and nonaqueous pharmaceutical extending media, as for example, water, liquid polyethylene glycols, glycerol, aqueous alcohol, digestible oils and the like. Furthermore, suspending agents, as for example, lauryl sulfonates, long-chain fatty acid derivatives of polyalkylene oxides, sorbitan derivatives of polyalkylene oxides, sodium alkyl sulfates and the like can be employed. Additionally, preservatives, as for example, lower alkyl esters of p-hydroxybenzoic acid; flavoring agents, as for example, saccharin, sugars, synthetic food flavors and the like; thickening agents such as carboxyrnethylcellulose, gelatin, pectin and the like; buifering agents; and other pharmaceutical additaments can be employed as desired.

The following examples illustrate the preparation of the new acid addition salts, and the suspensions in which they are employed in combination.

Example 1 Preparation of the o-(4-hydroxybenzoyl)benzoic acid salt of N,N-dimethyl-N-(Z-thenyl)-N-(2-pyridyl)ethylenediamine.

To a solution of 22.4 g. of o-(4-hydroxybenzoyl)benzoic acid and 6.2 g. of sodium carbonate in 1500 ml. of water was added slowly and with stirring a solution of 29.8 g. of N,N-dimethyl-N-(Z-thenyl)-N'-(2-pyridyl)- ethylenediamine dihydroehloride in 500 ml. of water. Crystals began to form as the latter solution was added, and stirring was continued until all of the solution had been added. The precipitated o-(4-hydroxybenzoyl)- benzoic acid salt of N,N-dimethyl-N-(2-thenyl)-N-(2- pyridyl)ethylenediamine was removed and washed with hot Water. The salt was substantially water-insoluble, and melted at about l84-185 C.

Example 2 Preparation of the o-(4-hydroxybenzoyl)benzoic acid salt of 1-cyclopentylZ-methylaminopropane.

A solution of the sodium salt of o-(4-hydroxybenzoyl)- benzoic acid was prepared by dissolving 6.2 g. of sodium carbonate monohydrate and 24.2 g. of o-(4-hydroxybenzoyl)benzoic acid in about 1500 ml. of water. The resulting solution was filtered, and thereto was added, slowly and with stirring, a filtered solution of 17.7 g. of l-cyclopentyl-Z-methylaminopropane hydrochloride in 500 ml. of water. A crystalline precipitate of the o-(4- hydroxybenzoyl)benzoic acid salt of l-cyclopentyl-2- methylaminopropane formed. The precipitate was removed by filtration, washed with water and dried. The o-(4-hydroxybenzoyl)benzoic acid salt of 1-cyclopropyl- 2-methylaminopropane thus prepared was a crystalline substance which was practically insoluble in water and organic solvents. Although substantially pure at this point, 1 cyclopentyl 2 methylaminopropane o (4 hydroxybenzoyl)benzoate could be recrystallized by preparing a saturated solution of the salt in hot poly ethylene glycol 200, filtering hot, and cooling.

The o-(4-hydroxybenzoyl)benzoic acid salt of l-cyclopentyl-Z-methylaminopropane melted at about 184185 C. When approximately equal amounts of the o-(4- hydroxybenzoyl)benzoic acid salts of 1-cyclopentyl-2- methylaminopropane and N,N-dimethyl-N-(2-thenyl)- N'-(2-pyridyl)ethylenediamine were mixed, the melting point of the mixture was about 165 C.

Example 3 Preparation of the 1,5-naphthalene disulfonic acid salt of 1-p-chlorophenyl-2-phenyl-4-pyrrolidino-2-butene.

To a solution of 20 g. of 1-p-chlor0phenyl-2-phenyl4- pyrrolidino-Z-butene diphosphate in 200 ml. of distilled Water warmed to 60 C. was added slowly and with stirring a solution of 7.26 g. of disodium 1,5-naphthalene disulfonate dihydrate in 100 ml. of water warmed to about 60 C. The mixture was stirred at room temperature until precipitation was completed and the temperature of the mixture had reached about 25 C. The 1,5- naphthalene disulfonic acid salt of l-p-chlorophenyl-Z- phenyl-4-pyrrolidino-Z-butene thus prepared was collected and washed with distilled water. The salt is substantially insoluble in water.

Di-( l-p-chlorophenyl-Z-phenyl-4-pyrrolidino-2-butene) 1,5-naphthalene disulfonate thus prepared melted at about 212-213 C.

The following examples will illustrate the preparation of pharmaceutical suspensions embodying the novel concepts of this invention.

Example 4 The following powdered ingredients are blended until a uniform mixture has been achieved:

Sucrose 500 Methyl-p-hydroxybenzoate 0.3 'Propyl-p-hydroxybenzoate 0.3 Butyl-p-hydroxybenzoate 0. 1 5 Sodium carboxymethylcellulose 330 Methyl cellulose HG 1500 2.5 Soluble saccharin 1.0 Magnesium sulfate 1.5 o-(4-hydroxybenzoyl)benzoic acid salt of N,N-

dimethyl N (2 thenyl) N (2 pyridyl)- ethylenediamine 4.5 o-(4-hydroxybenzoyl)benzoic acid salt of 1- cyclopentyl-2-methylaminopropane 2.83 1,5-naphthalene disulfonic acid salt of l-pchlorophenyl 2 phenyl 4 pyrrolidino 2 butene 1.42 Sodium chloride 2.0

When the stated ingredients have been thoroughly mixed, the powder is added to 200 ml. of water while stirring, and stirring is continued until the mixture is smooth and uniform. While continuing stirring, 250 g. of aluminum hydroxide gel are added and stirring is continued until no more lumps of aluminum hydroxide are present. To the uniform slurry thus obtained are added 2.0 ml. of a 10 per cent aqueous solution of F. D. and C. yellow food coloring number 5, 2.0 ml. of a 10 per cent alcoholic solution of chocolate cream flavor and 1.0 ml. of a 10 per cent alcoholic solution of imitation coconut custard flavor. The resulting mixture is diluted with water to make a total final volume of 1 liter, stirred, and homogenized at a pressure of 2500 lb. per square inch.

The suspension thus prepared contains in each ml. the equivalent of about 1 mg. of 1-p-chlorophenyl-2-phenyl- 4-pyrrolidino-2-butene base, 2.2 mg. of N,N-dimethyl- N-(2-thenyl)-N'-(2-pyridyl)ethylenediamine base and about 1 mg. of 1-cyc1opentyl-2-methylaminopropane base.

Example 5 The following ingredients are blended until uniformly mixed:

G. Sodium carboxymethyleellulose 330 10 N,N dimethyl N (2 thenyl) N (2 pyridyl) ethylenediamine o (4 hydroxybenzoyl)-benzoate l0 1 cyclopentyl 2 methylaminopropane o (4 hydroxybenzoyl)benzoate 5 Di (1 p chlorophenyl 2 phenyl 4 pyrrolidino 2 butene) 1,5 naphthalene disulfonate 6 Methyl-p-hydroxybenzoate 0.5 Sodium lauryl sulfonate 0.3

. the equivalent of about 4 mg. of 1-pchlorophenyl-2- phenyl-4-pyrrolidino-2-butene base, about 5 mg. of N,N dimethyl-N-(2 thenyl)-N-(2 pyridyl)ethylenediamine base and about 2 mg. of 1-cyclopentyl-2-methylaminopropane base.

Example 6 The following powdered ingredients are thoroughly mixed:

After the powdered ingredients have been thoroughly mixed, they are added to 200 ml. of water while stirring, and stirred until the mixture is smooth and uniform. Stirring is continued while the volume of the suspension is brought to 1 liter by the addition of water. The resulting suspension contains in each milliliter the equiv- H alent of about 0.5 mg. of 1p-chlorophenyl-2-phenyl-4- pyrrolidino-2-butene base, 1 mg. of N,N-dimethyl-N'- (Z-thenyl)-N-(2-pyridyl)ethylenediamine base and 0.5 mg. of 1-cyclopentyl-2-methylaminopropane base.

We claim:

1. A pharmaceutical preparation comprising a suspension in a pharmaceutical suspending medium of therapeutically effective amounts of the o-(4-hydroxybenzoyl)benzoic acid salt of N,N-dimethyl-N-(2-thenyl)- N-(2pyridyl)ethylenediamine, the 1,5-naphthalene disulfonic acid salt of 1-p-chlorophenyl-2-phenyl-4-pyrrolidino-Z-butene and the o-(4-hydroxybenzoyl)benzoic acid salt of 1cyclopentyl-2-methy1aminopropane.

2. A therapeutic composition comprising an aqueous suspension of the o-(4-hydroxybenzoyl)benzoic acid salt of N,N-dimethyl-N'-(2-thenyl) -N- (2-pyridyl) ethylenediamine, the o-(4-hydroxybenzoyl)benzoic acid salt of 1-cyclopentyl-2-methylaminopropane, and the 1,5-naphthalene disulfonic acid salt of 1-p-chlorophenyl-2-phenyl- 4-pyrrolidino-2-butene.

3. A therapeutic suspension containing about 2 to 10 mg./ml. of the o-(4-hydroxybenzoyl)benzoic acid salt of N,N-dimethyl-N'- 2-thenyl) -N'( 2-pyridyl) ethylenediamine, about 1 to 6 mg./ml. of the 1,5-naphthalene disulfonic acid salt of 1-p-chlorophenyl-2-phenyl-4-pyrrolidino-2-butcne and about 1 to 5 mg./ml. of the 0-(4- hydroxybenzoyl)benzoic acid salt of 1-cyclopentyl-2- methylaminopropane.

4. A therapeutic suspension containing in each milliliter thereof about 4.5 mg. of the o-(4-hydroxybenzoyl)- benzoic acid salt of N,N-dirnethyl-N-(2-thenyl)-N-(2- pyridyl)ethy1enediamine, about 3 mg. of the o-(4-hydroxybenzoyDbenzoic acid salt of 1-cyclopentyl-2-methylaminopropane, and about 1.5 mg. of the 1,5-naphthalene disulfonic acid salt of 1-p-chlorophenyl-Z-phenyl-4- pyrrolidino-Z-butene.

References Cited in the file of this patent Leonard et al., Histamine Antagonists Review Number 3, Chemical-Biological Coordination Center, National Research Council, 1950, Washington, p. 25. 

1. A PHARMACEUTICAL PREPARATION COMPRISING A SUSPENSION IN A PHARMACEUTICAL SUSPENDING MEDIUM OF THERAPEUTICALLY EFFECTIVE AMOUNTS OF THE O-(4-HYDROXYBENZOYL) BENZOIC ACID SALT OF N,N-DIMETHYL-N''-(2-THENYL)N''-(2-PYRIDYL) ETHYLENEDIAMINE, THE 1,5-NAPHTHALENE DISULFONIC ACID SALT OF 1-P-CHLOROPHENYL-2-PHENYL-4-PYRROLIDINO-2-BUTENE AND THE O-(4-HYDROXYBENZOYL) BENZOIC ACID SALT OF 1-CYCLOPENTYL-2-METHYLAMINOPROPANE. 